PROJECT SUMMARY: A consequence of modernization is that people have adopted diets for which they are poorly adapted and live inactive lifestyles. This has resulted in dramatic increases in obesity, dyslipidemias, Type 2 diabetes, as well as other aggregates of the Metabolic Syndrome. Metabolic dysregulation of the liver is an early and prominent defect in the sequalae that lead to these conditions. A primary defect evident in the liver is a selective insulin resistance characterized by an impairment in insulin suppression of endogenous glucose production (EGP), but intact lipogenesis and lipid storage. This creates impaired regulation of blood glucose and an unhealthy accumulation of fat in the liver. Liver fibrosis is closely correlated to insulin resistance. We have compelling evidence that the cell ?adhesome? couples changes in liver extracellular matrix to insulin resistance. The adhesome consists of integrin ?? heterodimers that transmit extracellular signals to protein complexes necessary for cells to adapt to their environment. We found that disruption of the adhesome either by disrupting the integrin ?1 subunit or by deletion of the integrin-linked kinase (ILK) in the cell prevents fatty liver in obese mice. Interestingly, only ILK deletion prevents resistance to insulin suppression of GP. The proposed studies will define how the cell adhesome is coupled to hepatic metabolic regulation. Studies will use genetic mouse models to test the hypotheses that i) deleterious effects of ILK in the liver of diet-induced obese mice require that it complex with binding partners, PINCH and parvin; ii) ILK deletion reverses pre-existing fatty liver and IR in diet- induced obese mice; and iii) ILK requires Itg?1 for its metabolic effects in DIO mice. These hypotheses will be addressed using isotopic methods to measure fatty acid synthesis and liver fatty acid uptake, triglyceride formation and export, and glucose fluxes in catheterized, conscious genetic mouse models. Hepatocytes will be isolated from these mouse models to define mechanisms that are particularly complex in the whole organism. Biochemical and histological analyses will identify pathways and regulatory mechanisms involved in metabolic regulation of nutrient fluxes by the cell adhesome of lean and diet-induced obese mice. Functional tests of the endoplasmic reticulum and mitochondria will define the role of these systems essential to fatty acid synthesis and nutrient oxidation, respectively. These studies will define the role of the cell adhesome in obesity-related liver metabolic disease and it will identify potential targets for treating the metabolic effects of obesity on the liver.